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COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial

The post-pericardiotomy syndrome (PPS) is a common complication of cardiac surgery, that can prolong recovery of the patient and duration of hospitalization, but also be significantly disabling and even life-threatening [1]. The size and site of pericardial effusion are related to the type of surgery, periprocedural medications, and individual response to surgical trauma. Cardiac tamponade is more common following valve surgery (73%) than coronary artery bypass grafting (CABG) alone (24%) and may be related to the preoperative use of anticoagulants [2]. Most cases of cardiac tamponade occur more than 7 days after surgery, and may develop slowly, without clear-cut clinical signs [2,3]. Independent risk factors for development of large pericardial effusion in PPS are also larger body surface area, pulmonary thromboembolism, hypertension, immunosuppression, renal failure, urgency of operation, surgical procedure other than coronary artery bypass grafting, and prolonged cardiopulmonary bypass [4]. Cardiac tamponade after cardiac surgery may also be caused by intrapericardial haematoma which most often spontaneously resolve but may also require urgent evacuation. Constrictive pericarditis may also occur after cardiac surgery. Warfarin administration in patients with early postoperative pericardial effusion imposes the greatest risk, particularly in those who did not undergo pericardiocentesis and drainage of the effusion [5].

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce the size of asymptomatic postoperative pericardial effusions (in 77% of the patients in one large study [3]. However, only one previous study [6] has shown the efficacy of NSAIDs for this condition and since patients who have recently had heart surgery are fragile, it is important to understand the balance of risks and benefits for this treatment. Although NSAIDs are usually given for only a short time to patients with pericardial effusions, they can cause serious adverse effects, such as upper gastrointestinal tract bleeding or perforation [7], but also myocardial infarction, acute heart failure, and acute renal failure [8]. In the February issue of this Newsletter, we have already commented the randomized study of Meurin et al. [9] performed in 5 French postoperative cardiac rehabilitation centres, including 196 patients with moderate to large persistent pericardial effusion more than 7 days after cardiac surgery. The patients were randomly assigned to diclofenac, 50 mg, or placebo twice daily for 14 days. Eleven cases of late cardiac tamponade occurred in the placebo group and 9 in the diclofenac group (P=0.64). These differences persisted after adjustment for grade of pericardial effusion at baseline, treatment site, and type of surgery. Therefore, in this trial, the use of diclofenac, 100 mg/d, did not significantly reduce the size of pericardial effusions or the risk for late cardiac tamponade. Moreover, this study confirmed that moderate to large pericardial effusion (grade 2, 3, or 4) occurring 7 to 30 days after cardiac surgery is a severe condition because 10.2% of these patients required pericardiocentesis in the 14 days after they were enrolled in the study. Obviously, an alternative option for treatment and prevention was needed.

Summary of the paper

At the hotline session of the this year European Society of Cardiology (ESC) Congress in Stockholm, Massimo Imazio presented the results of the COPPS trial (COlchicine for the Prevention of the Post-pericardiotomy Syndrome) which was published on the very same day as the fast-track ESC clinical trial update in the European Heart Journal [10]. The aim of the COPPS trial was to test the efficacy and safety of colchicine for the primary prevention of the post-pericardiotomy syndrome. The COPPS study was performed in 6 Italian centres, as a double-blind, randomized, non-commercial trial. On the third post-operative day, 360 patients (mean age 65.7+12.3 years, 66% males), 180 in each treatment arm, were randomized to receive placebo or colchicine (1.0 mg twice daily for the first day followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients ≥70 kg, and half of the doses for patients weighting less than 70 kg or intolerant to the highest dose). The primary efficacy endpoint was the incidence of post-pericardiotomy syndrome at 12 months. Secondary endpoint was the combined rate of disease-related hospitalization, cardiac tamponade, constrictive pericarditis, and relapses. Colchicine significantly reduced the incidence of the post-pericardiotomy syndrome at 12 months compared with placebo (respectively, 8.9 vs. 21.1%; P=0.002; number needed to treat - 8). Colchicine also reduced the secondary endpoint (respectively, 0.6 vs. 5.0%; P=0.024). The rate of side effects (mainly related to gastrointestinal intolerance) was similar in the colchicine and placebo groups (respectively, 8.9 vs. 5.0%; P=0.212).

Myocardial Disease


Discussion

The COPPS trial was designed to assess the efficacy and safety of colchicine for the primary prevention of the PPS. This study is an important step ahead in the series of randomized trials addressing important issues in the management of pericardial diseases, designed and conducted by Massimo Imazio. Colchicine is efficacious, inexpensive, and safe medication proven for the treatment and prevention of pericarditis. The exact mechanism of colchicine action is not fully understood. Most of the pharmacological effects of colchicine on cells involved in inflammation appear to be related to its capacity to disrupt microtubules.[10] Colchicine inhibits the process of microtubule self-assembly by binding b-tubulin with the formation of tubulin–colchicine complexes. This action takes place either in the mitotic spindle or in the interphase stage, thus colchicine inhibits the movement of intercellular granules and the secretion of various substances. By this mechanism, colchicine is able to inhibit various leucocytes functions, and this effect should be the most significant for the anti-inflammatory action. Moreover, colchicine shows a preferential concentration in leucocytes and its peak concentration may be more than 16 times the peak concentration in plasma. This seems to be related to its therapeutic effect.

In the COPPS study, colchicine significantly reduced the incidence of the PPS and its related complications providing evidence for the first time that pharmacological prevention of the PSS is possible and safe. Most of the PPS events (85% of all PPS) occurred in the first month, and thus a preventive treatment with colchicine for the first 4 weeks following surgery seems appropriate. No severe side effects were documented, and gastrointestinal side effects were equally distributed between the colchicine and placebo groups. Diarrhoea is relatively common, affecting up to 10% of patients on colchicine treatment for pericarditis. The use of weight-adjusted doses without a loading dose and especially lower doses (i.e.
0.5 mg/day to 0.5 mg bid.) may be a way to reduce this side effect, improving drug compliance. The major study limitation is related to the definition of the PPS since there is no general agreement on this issue. The definition used in the study was taken from the preliminary study from Israel [11] assuming that the diagnosis can be established If at least 2 out of the following 5 diagnostic criteria are present:

  1. Fever lasting beyond the first post-operative week without evidence of systemic or focal infection
  2. Pleuritic chest pain
  3. Friction rub
  4. Evidence of pleural effusion
  5. Evidence of new or worsening pericardial effusion

Nevertheless, in the COPPS study, colchicine showed to reduce all 5 above listed major components of the PPS showing a true preventive effect even on several components of the pleuro-pericardial involvement after cardiac surgery.

Although postoperative pericardial effusion is frequent and potentially severe, few randomized, controlled trials have examined treatment for this condition. Recommendation given in the ESC Guidelines [12] to treat postoperative pericardial effusion with NSAIDs was based on the results of the double-blind, placebo-controlled, randomized study by Horneffer et al. [13] applying a 10-day course of ibuprofen or indomethacin. Of 1019 adult patients undergoing cardiac operations during a 14-month period, a diagnosis of postpericardiotomy syndrome was made in 187, and 149 were enrolled in the study. Diagnosis was based on the presence of at least two of the following: fever, anterior chest pain, and friction rub. Drug efficacy was defined as the resolution of at least two of these criteria within 48 hours of drug initiation. Ibuprofen and indomethacin were 90.2% and 88.7% effective, respectively, and both were significantly more effective than placebo (62.5%, p = 0.003). The occurrence of side effects, including nausea, vomiting, renal failure, and fluid retention, was low in all groups (13.1% for ibuprofen, 16.1% for indomethacin, and 16.7% for placebo [p = not significant). Length of hospital stay, incidence of ischemic events, and accumulation of significant pericardial effusions were similar in all groups. The results of this study suggested that both ibuprofen and indomethacin provide safe and effective symptomatic treatment for postpericardiotomy syndrome.

The COPPS trial was designed according to the results of the preliminary prospective, randomized, double-blind study on primary prevention of postpericardiotomy syndrome performed by Finkelstein et al [11] in 163 patients who underwent cardiac surgery in two centres in Israel. On the 3rd postoperative day, the patients were randomly assigned to receive colchicine (1.5 mg/day) or placebo for 1 month. All were evaluated monthly for the first 3 postoperative months for development of postpericardiotomy syndrome. Of the 111 patients who completed the study, 47 (42.3%) received colchicine and 64 (57.7%) placebo. There was no statistically significant difference between the groups in clinical or surgical characteristics. The postpericardiotomy syndrome was diagnosed in 19 patients (17.1%), 5/47 cases (10.6%) in the colchicine group and 14/64 (21.9%) in the placebo group. However the study was underpowered and the difference showed only a trend toward statistical significance (p < 0.135). This dilemma was resolved by the COPPS trial that was sufficiently powered to address this important question.

 

Conclusion:

Colchicine is safe and efficacious in the primary prevention of the PPS and its related complications and may halve the risk of developing the syndrome following cardiac surgery. Such a finding is particularly important for clinical practice because the post-operative management may be complex, troublesome and empirical anti-inflammatory therapy may not be efficacious. Primary prevention of postperiocardiotomy syndrome using short-term perioperative steroid treatment or intrapericardial steroid treatment or its combination with colchicine should be still further evaluated.

 

References


 

  1. Erlich JF, Paz Z. Postpericardial injury syndrome: an autoimmune phenomenon. Clin Rev Allergy Immunol. 2010;38(2-3):156-8.

  2. Kuvin JT, Harati NA, Pandian NG et al. Postoperative cardiac tamponade in the modern surgical era. Ann Thorac Surg 2002;74(4):1148-53.

  3. Tsang TS, Barnes ME, Hayes SN, Freeman WK, Dearani JA, Butler SL, et al. Clinical and echocardiographic characteristics of significant pericardial effusions following cardiothoracic surgery and outcomes of echo-guided pericardiocentesis for management: Mayo Clinic experience, 1979-1998. Chest. 1999;116:322-31.

  4. Ashikhmina EA, Schaff HV, Sinak LJ, Li Z, Dearani JA, Suri RM, Park SJ, Orszulak TA, Sundt TM 3rd. Pericardial effusion after cardiac surgery: risk factors, patient profiles, and contemporary management. Ann Thorac Surg 2010;89(1):112-8.

  5. Matsuyama K, Matsumoto M, Sugita T et al. Clinical characteristics of patients with constrictive pericarditis after coronary bypass surgery. Jpn Circ J 2001;65(6):480-2.

  6. Horneffer PJ, Miller RH, Pearson TA et al. The effective treatment of postpericardiotomy syndrome after cardiac operations. A randomized placebo-controlled trial. J Thorac Cardiovasc Surg 1990;100(2):292-6.

  7. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 2007;5:19-34.

  8. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA; American Heart Association. Use of nonsteroidal anti-inflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115:1634-42.

  9. Meurin P, Tabet JY, Thabut G, Cristofini P, Farrokhi T, Fischbach M, Pierre B, Driss AB, Renaud N, Iliou MC, Weber H; French Society of Cardiology. Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion: a multicenter randomized, double-blind trial. Ann Intern Med 2010;152(3):137-43.

  10. Imazio M, Trinchero R, Brucato A, Rovere ME, Gandino A, Cemin R, Ferrua S, Maestroni S, Zingarelli E, Barosi A, Simon C, Sansone F, Patrini D, Vitali E, Ferrazzi P, Spodick DH, Adler Y; on behalf of the COPPS Investigators. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J. 2010 Aug 30; [Epub ahead of print]

  11. Finkelstein Y, Shemesh J, Mahlab K et al. Colchicine for the prevention of postpericardiotomy syndrome. Herz 2002;27:791-4.

  12. Maisch B, Seferovic PM, Ristic AD, et al. Task Force on the Diagnosis and Manage-ment of Pericardial Diseases of the European Society of Cardiology. Guidelines on the diagnosis and management of pericardial diseases. Executive summary. Eur Heart J 2004;25(7):587-610.

  13. Horneffer PJ, Miller RH, Pearson TA, Rykiel MF, Reitz BA, Gardner TJ. The effective treatment of postpericardiotomy syndrome after cardiac operations. A randomized placebo-controlled trial. J Thorac Cardiovasc Surg. 1990;100(2):292-6.

     

Notes to editor


Imazio M, Trinchero R, Brucato A, Rovere ME, Gandino A, Cemin R, Ferrua S, Maestroni S, Zingarelli E, Barosi A, Simon C, Sansone F, Patrini D, Vitali E, Ferrazzi P, Spodick DH, Adler Y; on behalf of the COPPS Investigators.
Eur Heart J. 2010 Aug 30; [Epub ahead of print]

Presented by Arsen D. Ristić, MD, PhD, FESC
Assoc. Prof. of Internal Medicine – Cardiology, Dpt of Cardiology of the Clinical Center of Serbia, Belgrade University School of Medicine, Koste Todorovića 8, 11000 Belgrade, Serbia

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.